Stromal cells provide structural support for malignant cells, modulate the tumor microenvironment, and influence phenotypic behavior as well as the aggressiveness of the malignancy. In response, the tumor provides growth factors, cytokines, and cellular signals that continually initiate new stromal reactions and recruit new cells into the microenvironment to further support tumor growth. It is not fully understood how stroma influences the neoplastic cells, but there is evidence for involvement of soluble paracrine factors, extracellular matrix formation, and direct cell-to-cell interaction. Therefore, it might be possible to manipulate the tissue stromal cells and thereby interfere with the stroma-tumor interactions for therapeutic benefit. The prerequisite for this approach is that stromal cells be accessible to therapeutic manipulation. We have previously demonstrated that bone marrow-derived mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements and contribute to the development of tumors. Importantly, MSC are precursors of structural and supportive tissues and have been implicated in the repair of damaged tissues and in wound healing. Of interest is that the tumor microenvironment appears to exhibit cytokine profiles and cellular signals similar to those characteristics of wounded or damaged tissues. Given this, we hypothesized that MSC would home to and selectively proliferate in the tumor microenvironment and that gene-modified MSC could be used as cellular vehicles to deliver gene products into tumors. Our preliminary data suggests that MSC home to and participate in tumor stroma formation in both subcutaneous and Intraperitoneal tumor xenografts in mice. Additionally, once homed to tumor beds, MSC proliferate rapidly and integrate. Our proposed studies aim at understanding the factors that influence MSC homing and selective proliferation in the tumor microenvironment. Additionally, our goals focus on optimizing the cellular delivery of therapeutic genes into the stroma of metastatic and subcutaneous tumor xenografts.